1. Field of the Invention
The invention is in the field of organic chemistry. The invention relates to an efficient process for conversion of commercially available (3R,3′R,6′R)-lutein containing 5-7% (3R,3′R)-zeaxanthin to (3R,6′R)-α-cryptoxanthin, (3R)-β-cryptoxanthin, anhydroluteins I, II, and III (dehydration products of lutein), and a method for separating and purifying the individual carotenoids including the unreacted (3R,3′R)-zeaxanthin. The invention also includes two methods that transform (3R,3′R,6′R)-lutein into (3R,6′R)-α-cryptoxanthin in excellent yields.
2. Related Art
(3R,6′R)-α-Cryptoxanthin, (3R)-β-cryptoxanthin, (3R,6′R)-anhydrolutein I ((3R,6′R)-3′,4′-didehydro-β,γ-caroten-3-ol), (3R,6′R)-2′,3′-anhydrolutein II ((3R,6′R)-2′,3′-didehydro-β,ε-caroten-3-ol), (3R)-3′,4′-anhydrolutein III ((3R)-3′,4′-didehydro-β,β-caroten-3-ol), and (3R,3′R)-zeaxanthin are among the major dietary carotenoids that are found in human serum, milk, major organs, and tissues. The chemical structures of these carotenoids are shown in Scheme 1. In view of the biological activity of carotenoids in the prevention of chronic diseases such as cancer, age-related macular degeneration, and cardiovascular disease, industrial production of a wide range of purified carotenoids is of great importance. While several dietary carotenoids, i.e. β-carotene, (3R,3′R,6′R)-lutein, and lycopene, are commercially available in various formulations as nutritional supplements and food coloring additives, the production of other serum carotenoids has not yet received much attention. In particular, (3R,6′R)-α-cryptoxanthin and (3R)-β-cryptoxanthin are among the rare carotenoids in nature and as a result extraction and isolation of these carotenoids from natural products on industrial scale is not economically viable. 
Meanwhile, the natural occurrence of anhydroluteins I, II, and III is uncertain. These carotenoids are presumably formed from acid-catalyzed dehydration of dietary (3R,3′R,6′R)-lutein in the human digestive system.
The total syntheses of (3R,6′R,)-α-cryptoxanthin and (3R)-β-cryptoxanthin has been reported by several researchers (Isler, O. et al. Helv. Chim. Acta, 40:456, 1957; Loeber, D. E. et al. J. Chem. Soc. (C) 404, 1971). These synthetic methods involve numerous steps and are therefore quite costly and difficult to implement on industrial scale, (3R,6′R)-α-Cryptoxanthin has also been prepared by partial synthesis from lutein (Goodfellow at al., Chem. Comm. 1578, 1970). According to this procedure, lutein is first treated with pyridine-sulfur trioxide complex, and the resulting sulfate monoester is reduced with lithium aluminum hydride (LAH) to give (3R,6′R)-α-cryptoxanthin; the yield and the details of the reaction conditions were not provided. The application of this method to industrial production of (3R,6′R)-α-cryptoxanthin is not readily feasible because of the sensitivity of the reagents to air and moisture. Another difficulty is due to the fact that LAH reduction of carotenoids has to be conducted under controlled conditions to avoid degradation of the starting material and the formation of side products. In addition, this process does not appear to be suitable for the preparation of (3R)-β-cryptoxanthin.
There are several reports on the partial synthesis of (3R,6′R)-anhydrolutein I from (3R,3′R,6′R)-lutein. One published procedure involves treatment of (3R,3′R,6′R)-lutein with a boric acid-naphthalene melt (Zechmeister and Sease, J. Am. Chem. Soc., 65: 1951, 1943). However, under the conditions employed, the total yield of (3R,6′R)-anhydrolutein I based on (3R,3′R,6′R)-lutein was approximately 18%.
Another procedure is based on allylic reduction of (3R,3′R,6′R)-lutein employing aluminum chloride/lithium aluminum hydride (AlCl3/LiAlH4=3/1) (AlHCl2) complex (Buchecker et al., Helv. Chim. Acta 57: 631, 1974). While (3R,6′R)-anhydrolutein I has been obtained from (3R,3′R,6′R)-lutein in a good yield by this method, due to the sensitivity of the reagents to moisture and air, this process is difficult to scale up for industrial applications.
The most recent partial synthesis of anhydroluteins I, II, and III from (3R,3′R,6′R)-lutein has been reported by Khachik et al. (J. Chrom. Biomed. Appl., 670:219-233, 1995). This method employs 2% concentrated sulfuric acid in acetone to obtain a mixture of anhydroluteins I, II, and III in 92% total yield; among these (3R,6′R)-anhydrolutein I is the major product. While this method can be performed on industrial scale, its scope is limited to the preparation of only anhydroluteins.